Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug-resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)-targeted therapies.In this study, we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway.Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti-cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down-regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer.

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BackgroundPancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking.MethodsThrough bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo.ResultsL61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values in the range between 0.86 and 2.83 µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo.ConclusionCollectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer.

Internet-of-Things (IoT) devices are ubiquitous and growing rapidly in number. However, IoT manufacturers have focused on the functionality and features of the devices and made security an afterthought. Since IoT devices have small memory capacities and lowpower processors, many security firms have not been able to develop anti-malware software for these devices. Current IoT security solutions are heavy and unreliable. We have developed a lightweight IoT security solution that uses hacker tools against the hackers-in essence, a vaccine for IoT. Our software provides managed security and intelligence to IoT devices using a "friendly" botnet operated through a proven, existing communication infrastructure for distributed systems-the Bitcoin blockchain.

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